The long-term objectives of this program are to determine the physiological, biochemical, and molecular mechanisms by which thyroid hormone (TH) is responsible for mammalian brain development. The studies proposed in this application will focus on the effects of thyroid hormone on oligodendrocyte survival and development. Specifically, I will determine whether oligodendrocyte deficits in hypothyroid rat brain white matter tracts are a result of increased apoptosis or aberrant oligodendrocyte proliferation. To differentiate between these two hypotheses I will quantitate the total number of oligodendrocytes undergoing apoptosis during discrete stages of development. In comparison we will also assess the effects of TH on oligodendrocyte proliferation. Additionally, I will determine how IGF- I is regulated in the hypothyroid rat brain, and evaluate its role as an effector molecule of oligodendrocyte apoptosis. I will evaluate both the mRNA and protein expression patterns of IGF- 1 in the hypothyroid rat brain. If these experiments indicate a role for TH's effects on the IGF-1 axis, I will then attempt to test this hypothesis by simulating IGF-l over expression in vivo. These studies will provide significant insight towards the pathophysiologic mechanisms of hypothyroidism on the developing central nervous system.